Jason SchnellStructure and function of membrane proteins and their interactions with small molecules and the lipid bilayer

Co-workers: Dr. Anu Chandran, Felipe Ossa, Muhd Mohd Kipli.

We are interested in understanding the structure and function of membrane proteins, especially those implicated in human health and disease. More specifically, our research aims to identify the molecular basis of the interactions between membrane proteins and the components of the membrane bilayer (e.g., lipids and cholesterol), other proteins, and drug-like small molecules; ultimately, we are interested in how these interactions lead to events on the cellular level. Current research is focused on three systems:

Influenza matrix protein 2: One system under investigation is the matrix protein 2 (M2) from influenza. The influenza virus is easily spreadable between people and can result in severe illness and death, particularly for young children and older adults. Globally, 3-5 million people suffer severe illness and 250,000-500,000 people die from influenza every year (World Health Organization estimates). We are studying the lipid interactions of the ‘swine flu’ M2 to better understand its role in new virus assembly and membrane scission.

Sigma-1 Receptor: A second research area is on the human Sigma-1 Receptor (S1R), which is found primarily in the endoplasmic reticulum (ER) and is a ligand-regulated membrane protein chaperone involved in the ER stress response. The activity of S1R, which includes the regulation of ion channels at the plasma membrane, has been linked to a range of diseases of the central nervous system (CNS), including schizophrenia, Alzheimer’s and Parkinson’s, amnesia, depression, amyotrophic lateral sclerosis, and addiction. As a result, S1R is being

explored as a pharmaceutical target, and our aim is to facilitate this research by providing a greater understanding of the S1R structure and dynamics, and its interactions with other proteins and small molecules.

DP1/Reticulon family: A third research area is the DP1/Reticulon family of integral membrane proteins. Members of this protein family are responsible for maintaining the high membrane curvature of the tubular ER, and mutations in these proteins are implicated in neuronal diseases such as Hereditary Spastic Paraplegia. To gain insight into how this class of proteins curve and remodel lipid membranes – and how they malfunction in disease – we have focused on the protein Yop1p, which is a DP1 family member from Saccharomyces cerevisiae.

A central technique of our laboratory is solution nuclear magnetic resonance (NMR) spectroscopy, which allows atomic-level studies of protein structures and their interactions with lipids and small molecules. NMR can be uniquely informative in situations where the molecular conformations or interactions are dynamic or heterogeneous. However, a wide variety of biochemical and biophysical tools are brought to bear on the research questions, including electron microscopy, circular dichroism, fluorescence, electron microscopy, and analytical ultracentrifugation. We also have collaborations with various research groups around the world including virologists, cell biologists, and computational biologists.